Actinomycin D (AMD) is an unique biochemical agent which is extraordinarily effective against tumor cells. It is one of the very few agents which is curative of the two human cancer lines. However, the rapid accumulation of the major proportion of the administered AMD in the nucleated cells of the normal organs of the host compounded with the lack of its metabolic deactivation and insufficient elimination from the body renders this drug a highly toxic agent, unfavorable for prolonged use in patients. In order to fully utilize the maximum chemotherapeutic potential of this drug development of modified forms of actinomycin D which can demonstrate broader range of antitumor activity and reduced host toxicity appeared to be highly desirable. The gaol of our research has, therefore, been chemical modification of AMD generating new agents which will demonstrate improved effectiveness in a wide range of tumors and simultaneously will eliminate the undesirable toxicities in the patients. On the basis of chemical, biochemical, biophysical and pharmacological investigations we have been able to design and synthesize new drugs which demonstrate enhanced antitumor activity against malignant tumor lines and reduced host toxicity in experimental animals. We have found that in contrast to AMD the agents are metabolized and excreted at a fast rate in experimental animals. With the use of human tumor lines in tissue culture and leukemia and malanoma lines in animals we are continuing investigations to understand the mechanism of action of these newly snythesized agents. The overall objective of this research is to further optimize our effort in order to devise new agents which will eliminate the undesirable side effects of AMD and be more effective agents in the clinic.